A large fraction of cardiac output (i.e. greater than 50%) can be distributed to skin during heat stress, thus control of skin blood flow is vital for blood pressure regulation during a hypotensive challenge. Neural control of the cutaneous vasculature is unique relative to many vascular beds in that it is governed by both a sympathetic vasoconstrictor system and a separate sympathetic cholinergic active vasodilator system. Adding to this complexity, direct local heating of the skin induces cutaneous vasodilation via an entirely different mechanism (i.e. non-neural and primarily nitric oxide dependent). Moreover, profuse sweating that occurs during heat stress contributes to impaired blood pressure control if plasma volume is sufficiently reduced. Sweating occurs through the engagement of a sympathetic cholinergic system that may or may not be related to the cutaneous active vasodilator system. Classically, these systems (i.e. vasoconstrictor, vasodilator, and sweating systems) have been viewed as being independent, without one system affecting the other. However, preliminary data suggest significant interaction between these systems. In heat stressed individuals the degree of interaction and the importance of this interaction with respect to blood pressure and temperature regulation remain unclear. To this end, the projects outlined in this application will address the following three specific aims: 1) Test the hypothesis that substances released from the cutaneous active vasodilator nerve attenuate cutaneous vasoconstrictor responses through pre- and post- synaptic mechanisms;2) Test the hypothesis that local heating attenuates cutaneous vasoconstrictor responsiveness through nitric oxide dependent and independent mechanisms;3) Test the hypothesis that sweat glands are sensitized by mechanisms associated with local heating and through engagement of the cutaneous active vasodilator system. These objectives will be accomplished by combining the innovative technique of intradermal microdialysis to locally deliver pharmacological agents and regionally sample interstitial fluid, with the simultaneous assessment of skin blood flow and sweat rate. Findings from these studies will provide new insight into neural control of skin blood flow and sweating and how these responses can be affected by non-neural events. This information will prove valuable on two fronts: 1) it will identify mechanisms contributing to an increased incidence of fainting in heat stressed individuals, and 2) it will provide a valuable benchmark from which subsequent studies can be performed to better understand how neural and non-neural modulators of skin blood flow and sweating may be altered by disease (i.e. diabetes, heart failure, etc) and non-disease (i.e. aging) conditions.